Studies in our laboratory have shown that gamma-glutamyl derivatives of compounds containing an amino function are selectively accumulated and degraded to glutamate and the compound containing the amino function at the sites of localization of gamma-glutamyl transpeptidase. These sites primarily include the kidney, the endothelium of kidney and brain microvessels and also some epithelial cells having a secretory function (including the epithelium of bronchi and bronchioles). We therefore propose to study gamma-glutamyl derivatives of certain drugs with a well defined pharmacological activity. Such derivatives are expected to be accumulated at the sites of localization of the enzyme where the active drug would be released from its inactive precursor and exerts its activity. The effectiveness of this approach was demonstrated in preliminary studies in our laboratory by the synthesis of gamma-glutamyl DOPA (i.e., L-gamma-glutamyl-L-3,4-dihydroxyphenylalanine). Administration of this derivative to small laboratory animals leads to its preferential accumulation in the kidney, release of DOPA and its conversion to dopamine by the action of kidney aromatic amino acid decarboxylase. The dopamine that is selectively generated in the kidney exerts a potent local activity, increasing renal plasma flow and urine output. Because of this organ-specific activity, systemic effects and untoward reactions do not occur. We wish to extend our studies on the pharmacological activity of gamma-glutamyl DOPA in larger animals such as dogs, as a first step toward its application in human therapy. We also wish to initiate a program of synthesis and exploration of the pharmacological activity of other gamma-glutamyl derivatives of pharmacologically active substances such as gamma-glutamyl derivatives of -adrenergic agonists, certain diuretic drugs and antibacterial agents. Such derivatives should be potentially useful in the treatment of cardiovascular, pulmonary and renal disorders.